Summary - Core B: Non-human Primate and Imaging Core A major barrier to HIV cure is the persistence of HIV-1 infected cells that constitute the viral reservoir. While current antiretroviral combination therapies are able to inhibit viral replication to below detectable levels (50 copies) in the plasma of patient, ART cessation almost invariably leads to viral resurgence even in patients for which ART was initiated early post infection. This has led to the formulation of Shock and Kill approaches to activate and reduce the reservoirs using latency reversing agents under the umbrella of ART, though such approach in the absence of immunotherapy has not had any clinical benefit thus far. However, these results clearly indicate that long-term persistent HIV reservoirs are seeded rapidly post infection as confirmed it the nonhuman primate model of HIV. In addition, data from several groups and ours strongly suggest that residual viral replication is actually ongoing in various lymphoid tissues in spite of highly active ART, be it due to poor drug penetration, conversion or sanctuaries with limited antiviral immune contribution. In this application, we propose to quantify and map the early reservoir formation after vaginal infection and early ART intervention, using a series of state of the art imaging techniques as well detailed cellular analyses of the reservoirs obtained at various times of ART initiation. Next we propose to address the functional reservoir following prolonged ART and ART interruption, monitoring residual viral replication in tissues, sites of early viral rebound, the cellular origin of the active reservoir and immune interventions designed to bolster antiviral responses leading to antiviral control.